The principle objective of the proposed research is to develop methods for the rapid and efficient production of polycyclic nitrogen heterocycles. In particular, indolizidine and quinolizidine alkaloids, or larger molecules containing these ring systems are targeted. A large number of biologically active compounds are encompassed by these structural types. Hence, efficient and general synthetic methods are necessary for their construction. This will allow scientists to synthetically prepare alkaloids that are rare or nonexistent in nature, but are desired due to their biological activity. All of the synthetic methods proposed are based on the chemistry of the azido group. Intramolecular cycloaddition of azides with alkenes produces bicyclic triazolines, which are thermally labile heterocycles that may undergo certain types of rearrangements. In particular, they have a propensity to extrude dinitrogen, producing aziridines or imines. Part of the proposed research involves the exploitation of the chemistry of such products to form another ring. For example, cyclization of an azide with certain 1,3-dienes leads to the formation of pyrrolizidines and indolizidines in one synthetic operation. A more practical version has recently been developed, where an azide cyclizes with an alkene bearing a remote leaving group. The initial triazoline rearranges to an imine, which is alkylated intramolecularly to give a useful bicyclic iminium ion. A completely different method based on azide chemistry has also been developed. Certain alcohols and alkenes undergo ionization to a carbocation, which may be captured intramolecularly by an azide to form an aminodiazonium ion. One of the groups on a neighboring carbon atom then migrates to the nitrogen, displacing dinitrogen and leaving an iminium ion. A wide variety of bicyclic ring systems may be prepared by this method in principle, including bridged bicyclic rings. A major aspect of the proposal is the application of these methods to the synthesis of natural and unnatural alkaloids of interest using these methods. Nuphar alkaloids such as castoramine are important components in the fragrance industry. Dihydrocinchonine is a member of the Cinchona class of alkaloids, famous for antimalarial activity. Indolizidine 209B is a nicotinic receptor antagonist. Monomorine I is a trail pheromone of the pharaoh ant, a pest in heated buildings and a concern in hospitals. Some alkaloids of the lycorine class exhibit antitumor activity. 12b-Epizephyranthine and gamma-lycorane are members of this class that are targeted. Pictamine and the clavepictines are members of a new class of alkaloids that show cytotoxic activity. Arylquinolizidine alkaloids such as kayawongine and cryptopleurine are also interesting biologically, with the latter showing cytotoxic, vesicant, and anti-amoebicidal activity. Finally, some analogues of the important glycosidase inhibitors swainsonine and castanospermine are proposed. Preparation of quinolizidine ring analogues should improve the selectivity and potency of these compounds, which are under investigation as anticancer and anti-HIV drugs.